Project Summary After stunning improvements in patient outcomes for most childhood cancers in the latter half of the last century, cure rates have plateaued. Children with metastatic solid malignancies continue to have a less than 50% chance of survival despite being treated with highly intensive cytotoxic therapies. Neuroblastoma (NB), a diverse malignancy affecting very young children that arises from the developing sympathetic nervous system, is responsible for a disproportionate amount of morbidity and mortality attributable to childhood cancer and is the main focus of the Maris translational research program. Our primary motivation is to improve patient outcomes, and we also deem NB an outstanding model of cancer in general, such that discoveries of basic mechanisms of tumorigenesis are broadly applicable to other human malignancies. Over the next seven years, the Maris lab will seek to substantively improve cure rates for patients with through a multidisciplinary and collaborative research program. Our broad goal is to discover the fundamental mechanisms that subvert normal neural development and orchestrate NB tumorigenesis, and then to translate this knowledge into patient-specific therapies that will be more effective and less toxic. We thus have a comprehensive approach with six highly integrated major research efforts planned over the next seven years. 1) Genetic susceptibility to NB. Our lab has discovered the majority of NB predisposition genes using genetic approaches. We will now define the mechanisms by which DNA variation cause malignant transformation via epistatic deregulation of normal developmental pathways using epigenomics approaches. 2) NB genomics and clonal evolution. Our lab has led the collaborative efforts to define the genomic landscape of diagnostic high-risk NB. We will now focus on NB as a dynamic ecosystem, defining how tumors adapt to the selective pressure of therapy. 3) NB drug development. The Maris lab has utilized genomic data and genetic screens to define oncogenic vulnerabilities, and many of these have been translated to the clinic. We will now focus on defining mechanisms of therapy resistance to both standard of care agents and the targeted therapies we develop. 4) Immunogenomics. The Maris lab has used an integrative approach to discover several new immunotherapeutic targets in NB. We will now intensively focus on developing antibodies, antibody drug conjugate and adoptive T-cell therapies to these targets designed to eradicate NB safely. 5) Precision NB therapies. We have developed biomarker-directed clinical trials for children with relapsed NB, and will continue our efforts here both in the relapse and newly diagnosed setting using clinical trials designed to enrich for patients most likely to benefit. We think that our research program proposes a variety of innovative experimental strategies to uncover basic mechanisms of oncogenesis, kinome reprogramming, epigenetic adaptation and immune evasion, and is steadfastly translational. The significance of the proposed program is the discovery of fundamental mechanisms of NB tumorigenesis that will lead to markedly improved probability of cure coupled with reduced morbidity.